Improved glycaemic control in obese diabetic ob/ob mice using N-terminally modified gastric inhibitory polypeptide

Abstract

Gastric inhibitory polypeptide (GIP) is an important insulin-releasing hormone of the enteroinsular axis which is rapidly inactivated by the exopeptidase dipeptidyl peptidase (DPP) IV. The present study has examined the ability of Tyr 1 -glucitol GIP to be protected from plasma degradation and to enhance insulin-releasing and antihyperglycaemic activity in 20-to 25-week-old obese diabetic ob/ob mice. Degradation of GIP by incubation at 37 C with obese mouse plasma was clearly evident after 3 h (35% degraded). After 6 h, more than 61% of GIP was converted to GIP(3-42) whereas N-terminally modified Tyr 1 -glucitol GIP was resistant to degradation in plasma (>99% intact after 6 h). The formation of GIP(3-42) was almost completely abolished by inhibition of plasma DPP IV with diprotin A. Effects of GIP and Tyr -glucitol GIP also enhanced the glucose-lowering ability of 50 units/kg insulin (218·4 30·2 vs insulin alone 133·9 16·2 mmol/l.min; P<0·05). These data demonstrate that Tyr 1 -glucitol GIP displays resistance to plasma DPP IV degradation in a commonly used animal model of type 2 diabetes, resulting in enhanced antihyperglycaemic activity and insulin-releasing action in vivo.

International Union of Pharmacology. XXXV. The Glucagon Receptor Family

“…Conversely, glucagon receptor antagonists may potentially be useful for the treatment of diabetes mellitus (Zhang and Moller, 2000;Petersen and Sullivan, 2001;Ling et al, 2002). Similarly, GIP analogs continue to be assessed for potential utility in the treatment of type 2 diabetes (O'Harte et al, 1999(O'Harte et al, , 2000, and disruption of the murine GIP receptor gene promotes resistance to weight gain and enhanced energy expenditure, suggesting that GIP receptor antagonism merits consideration for the treatment of obesity (Miyawaki et GLUCAGON RECEPTOR FAMILY al., 2002). Similarly, dipeptidyl peptidase-IV-resistant analogs of GLP-1 and GLP-2 are in clinical trials for the treatment of diabetes and intestinal disorders, respectively (Drucker, 1999a(Drucker, , 2001a(Drucker, ,b, 2002.…”

Improved biological activity of Gly2- and Ser2-substituted analogues of glucose-dependent insulinotrophic polypeptide

“…Furthermore, NH 2 -terminal glucitol-GIP displayed markedly enhanced insulinotropic potency in clonal pancreatic -cells and improved in vivo biological activity in animals with type 2 diabetes (O'Harte et al 1998b(O'Harte et al , 2000. Based on these findings, and preliminary observations that substitution of the penultimate Ala 2 in GIP results in analogues with reduced DPP IV hydrolysis rates, we now report studies investigating the plasma stability, insulin-releasing activity and antihyperglycaemic properties of two novel NH 2 -terminal Ala …”

“…However, such structural modifications to the native GLP-1 molecule appear to impair receptor bindingactivation characteristics and insulinotropic activity, thereby compromising the benefits of protection from intrinsic DPP IV degradation. Recent studies in our laboratory have shown that an NH 2 -terminally glycated analogue of GIP (Tyr 1 -glucitol GIP) exhibits profound resistance to proteolytic DPP IV degradation, and displays enhanced cellular insulin-releasing and antihyperglycaemic activity in a commonly employed animal model of obesity-hyperinsulinaemic type 2 diabetes (O'Harte et al 1998b(O'Harte et al , 2000.…”

“…It is a combination of the above features that has aroused recent interest in the incretin hormones as novel potential therapeutic candidates for the treatment of type 2 diabetes (Bailey & Flatt 1995). To date, clinical trials have been limited to glucagon-like peptide-1 (GLP-1) (Holst 1999), although administration of an NH 2 -terminally glycated form of GIP with a prolonged circulating half-life has been shown to produce improved glucose tolerance in experimental animal models of diabetes (O'Harte et al 1999(O'Harte et al , 2000.…”

Development of neuropeptide drugs that cross the blood-brain barrier

“…91 Non-specific glycosylation was found to improve metabolic stability and increase activity of gastric inhibitory proteins. [92][93][94] This strategy has been used to increase the half-life of erythropoietin, another glycoprotein, with at least one variant being approved by the Food and Drug Administration for the treatment of anemia. 95 The increased stability induced by glycosylation has made it a focus for peptide drug examination / development.…”